Acta Diabetol 28: 229-232, 1992 ACTA DIABETOLOGICA 9 Springer-Verlag 1992 HI,A antigens in Italian type 1 diabetic patients: role of DR3/DR4 antigens and breast feeding in the onset of the disease E. Bognetti 1, E Meschi 1, C. Malavasi 1, M.R. Pastore 2, A. Sergi 2, M.T. llleni 3, C. Maffeis 4, L. Pinelli 4, and G. Chiumello 1 t Department of Paediatrics, Endocrine Unit, and 2 Department of Internal Medicine, San Raffaele Scientific Institute, University of Milan, Milan, Italy 3 Department of Immunohaematology, Istituto Nazionale dei Tumori, Milan, Italy 4 Department of Paediatrics, University of Verona, Verona, Italy Abstract. HLA-A, B, C, DR and DQ typing was per- formed in 381 Italian insulin-dependent diabetic patients and in 905 normal Italian subjects. The diabetic patients had significantly higher frequencies of HLA-Cw7, B8, B18, DR3, DR4, DQw2 and DQw3 and significantly lower frequencies of HLA-B17, Bw51, DR2, DR7 and DRwl 1. The frequency of heterozygosity for HLA-DR3/ DR4 was significantly higher in patients who developed the disease in the first 2 years of life and DR3 +/DR4-, DQw2 and DQw3 alleles were higher in those aged less than 14 years at onset. The HLA-DR4 allele was associ- ated with onset of diabetes in autumn and HLA-B 18 with onset in Autumn-winter. Diabetic children who were breast fed had a later onset of insulin-dependent diabetes mellitus than those who were bottle fed but these differ- ences were independent of HLA typing (11.18_+0.72 years vs 9.23_+0.42 years; mean+SEM). We conclude that: (1) in general, HLA distribution in Italian insulin- dependent diabetic patients reflects previous data re- ported in other European and North American popula- tions; (2) HLA-DR3 and DR4 are strongly associated with insulin-dependent diabetes in Italy as well, and these alleles seem to predispose to an earlier onset of the dis- ease; and (3) breast feeding may delay the onset of the disease. Key words: HLA - Insulin-dependent diabetes mellitus Breast feeding - Childhood Introduction The association between some HLA antigens and type 1 (insulin-dependent) diabetes mellitus has been widely ob- served by many authors [1-6]. The HLA system is thought to play an important role in physiological im- mune responses. HLA class II antigens, usually present Offprint requests to: E. Bognetti, Department of Paediatrics, San Raffaele ScientificInstitute, Via Olgettina, 60, 1-20132 Milan, Italy on antigen-presenting cells and on B lymphocytes, coop- erate with T helper lymphocytes in identifying foreign antigens. It has been suggested that the aberrant expres- sion of class II molecules on beta cell can trigger the autoimmune response leading to beta cell destruction [7]. Autoantigen recognition by helper T cells seems to be facilitated by the DR3 and DR4 molecules (serologically defined) [8], but DNA analyses by restriction fragment length polymorphism have suggested that the association of type 1 diabetes with DQ products is stronger than with those of DR [9, 10]. Previous HLA studies have shown considerable evi- dence for genetic heterogeneity within various popula- tions affected by the disease: HLA-DR3-positive patients more often have a milder form of disease, having less pronounced ketonuria at diagnosis, ketoacidotic symp- toms developing less often and experiencing a more pro- longed partial remission, compared to HLA-DR4 and DR3/DR4-positive patients [11]. Besides, some authors have shown that HLA-DR3/ DR4 and DR4 alleles are associated with an earlier onset of insulin-dependent diabetes mellitus compared to DR3- positive patients [4, 11]. Beyond genetic predisposition to insulin-dependent diabetes mellitus, it has been suggested that environmental factors modify the natural history of the disease, and breast feeding has been suggested as a potentially protective factor [12, 13]. The current study was designed to evaluate the rela- tionship between the genetic characteristics of a large Italian insulin-dependent diabetes cohort and the partic- ular environmental factors, sex and age at onset of dia- betes. Patients and methods We studied 381 Italian insulin-dependent diabetic patients (218 males, 163 females), of whom 377 were typed for A, B, C, 352 for DR and 260 for DQ. In this cohort insulin-dependent diabetes mellitus was diagnosed between 1958 and 1989 and the age at onset of the disease was 9.16_+5.55 years (mean+SD). At onset of dia- betes 304 patients were resident in Northern Italy, 69 patients in the south of Italy, 6 patients in central Italy and 2 patients in Sardinia.